Protease enzymes mediate many biological processes, e.g., by editing a polypeptide to a shorter, active form, or by terminating biological activity through degradation of an active polypeptide. Other protease enzymes are concerned with tissue remodeling.
Proteases hydrolyze the amide backbone of polypeptides and during this hydrolysis, a tetrahedral intermediate is formed as part of the enzyme-substrate complex. Some analogs of the tetrahedral intermediate can inhibit protease enzymes. Elements other than carbon, specifically, phosphorous and boron, have been used to prepare transition state analogs. Phosphorous: Kam, C.M.; Nishino, N.; Powers, J. C. , “Inhibition of Thermolysin and Carboxypeptidase A by Phosphoraridates”, Biochemistry 18, 3032-3038 (1979). Boron: Amiri, P.; Lindquist, R. N.; Matteson, D. S.; Sadhu, K. M. “Benzamidomethaneboronic Acid: Synthesis and Inhibition of Chymotrypsin”, Arch. Biochem. Biophys. 234, 531-536 (1984). There has been only one attempt, however, to utilize silanols in transition state analogs because silanediols have a strong proclivity to self condense and form siloxanes or silicones. The simplest silanediol, dimethylsilanediol, was tested as an inhibitor of angiotensin-converting enzyme and found to be inactive. Galardy, R. E.; Kortylewicz, Z. P. “Inhibitors of angiotensin-converting enzyme containing a tetrahedral arsenic atom”, Biochem. J. 226, 447-454 (1985). In addition, known silanediols are virtually all dialkyl or diaryl homologues. Lickiss, P. D., “The Synthesis and Structure of Organosilanols”, Adv. Inorg. Chem. 42, 147-262 (1995). Therefore, organic silanols have been absent from the field of protease inhibition.
It is an object of the invention to provide silicon-containing enzyme inhibitors.
It is a further object of the invention to provide silanols and silanediols and their siloxane oligomers as bioactive molecules, particularly as inhibitors of hydrolase enzymes.
It is a still further object of the invention to provide a process for the synthesis of silanol and silanediol-based peptide mimics as well as their siloxane oligomers.
It is yet another object to provide a method for inhibiting proteases using silicon-containing peptide analogs.